Spleen tyrosine kinase was first cloned from porcine spleen cDNA at the earliest time by Japanese scholar Taniguchi, et al. Its coding protein is a non-receptor tyrosine kinase, so it is named as spleen tyrosine kinase. The spleen tyrosine kinase plays an important role in the maturation of lymphocytes and the activation of immune cells. In recent years, it is found that SYK has abnormal expression in tumor, and SYK has close relation with a lot of signals that relate to tumorincidence, progression andmigration. SYK may be used as a target for treating tumors related to immune systems, such as lymphoma, leukemia and the like.
Entospletinib is an orally administered drug developed by Gilead. It is a selective Spleen tyrosine kinase (SYK) inhibitor, which inhibits the activity of spleen tyrosine kinase, and has a therapeutic effect on various diseases including cancer and inflammation. Entospletinib is in clinical studies for the treatment of patients with relapsed or refractory chronic lymphocytic leukemia. The chemical name of the drug is 6-(1H-indazole-6-yl))-N-[4-(4-morpholinyl))phenyl]imidazo [1,2-a]pyrazine-8-amine, and the structure of compound (I) is shown as below:

It is generally known that crystalline forms greatly affect drug's quality. Different crystalline forms may have remarkable difference in appearance, solubility, melting point, dissolution profile, bioavailability and so on, thus affect drug's stability, bioavailability and efficacy. Therefore, it is of great significance to develop novel and more suitable crystalline forms for drug development.
As is known to the skilled in the art, the presence of new solid polymorphs of a known chemical substance solid is unpredictable. The existence or the number of the polymorphs is also unpredictable. In addition, it is also unpredictable that under what conditions a specific form will crystallize, and what are the characteristics of the polymorphic form. Since different polymorphs have different properties (e.g., solubility, stability), their performances on drug's use and storage are different, it is necessary to study all solid forms, including all polymorphs to provide drugs with improved stability or solubility.
At present, only two hydrates of compound (I) dimesylate were reported in US20150038505A1, namely crystalline form 3 and crystalline form 7 (hereinafter referred to as prior form 3 and prior form 7). As reported in the prior art, the hygroscopicity of prior form 7 is very high under various humidity conditions. Relatively, prior form 3 is a more preferable crystalline form, because its hygroscopicity is relatively low under 70% humidity, and its solubility is significantly improved compared to the free base and amorphous monomesylate. However, the prior form 3 is found that it has 20% weight gain in high humidity conditions (above 80% humidity), and will convert to prior form 7 at 90% humidity, thus prior form 3 cannot meet the strict property requirements of crystal or drug product in industrial production and later drug development. Furthermore, although US20150038505A1 reported more than one method to obtain prior form 3, the methods are complicated and not easy to conduct. In addition, study on the particle size distribution showed that crystal grains size of prior form 3 and prior form 7 are too small to separate in production.
Accordingly, there is still a need to develop novel crystalline forms of compound (I) or its salts, which are more suitable to pharmaceutical formulations and can be obtained by more easily repeatable methods.